Hearing loss is a major health problem which affects more than 28 million Americans. Approximately two million persons are profoundly infants. About 40-60% of profound childhood deafness has been attributed to genetic causes and more than 175 different forms of hereditary deafness have been identified. Extensive genetic heterogeneity is found in hearing disorders and recognized forms account for only about one-third of all genetic cases. Despite the significant role of genetic factors in the etiology of deafness, little is known about specific genes which are involved in the hearing process or the molecular nature of disorders of these genes. The major goal of this proposed project is to use contemporary techniques of molecular biology to isolate and characterize genes involved in normal hearing. Because so little is known about genes which participate in auditory function, a "reverse molecular genetics" approach will be taken by constructing a cDNA library from human fetal cochlea. Identification and isolation of cochlear genes will be a key step in the molecular characterization of genes that cause deafness. This knowledge will undoubtedly contribute to better methods for earlier diagnosis, more precise genetic counseling, improved medical treatment, and, perhaps, even the prevention of deafness. The proposed experimental design and methods are: (1) to construct a cochlear cDNA library from human fetal cochlear poly A+ RNA, (2) to identify and isolate cochlear-specific genes, (3) to characterize cochlear genes at a molecular level including DNA sequence analysis, (4) to investigate the conservation of cochlear genes in other species, (5) to determine the chromosome localization for comparison to known map locations of hearing disorders, and for prospective mapping studies of deafness syndromes, (6) to study the specific cellular and developmental expression of the isolated genes, and (7) to characterize the protein products of the genes.